Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Wiegering, Antonia; Dildrop, Renate; Vesque, Christine; Schneider‐Maunoury, Sylvie; Gerhardt, Christoph

doi:10.1101/2020.02.10.942300

Cited by 4 publications

(3 citation statements)

References 93 publications

(135 reference statements)

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“…Regarding the impact of ANKS3 on the composition of TZ, the fact that the amount of NPHP1 is decreased under both mutant and KD_ANKS3 conditions is consistent with the downregulation of the Nphp1 transcript in mIMCD3 cells. Notably, the level of NPHP4 at TZ was not affected, which is expected because recruitment of NPHP4 to TZ does not require NPHP1 as shown in several cell types (38). In contrast, TMEM67 was absent from TZ in KD_ANKS3 cells while unchanged in P269L mutant cells.…”

Section: Discussionmentioning

confidence: 63%

The ANKS3/BICC1 protein complex is a master post-transcriptional regulator ofNPHP1ciliopathy-gene transcripts

Mahuzier,

Odye,

Grampa

et al. 2024

Preprint

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Ciliopathies are a class of multi-systemic genetic diseases characterized by ciliary dysfunction. Here, we report a novel ANKS3 variant in patients with a renal ciliopathy known as nephronophthisis (NPH) associated with hepatic defects. ANKS3 is an ankyrin and sterile alpha motif domain-containing protein that interacts with many NPH proteins as well as with BICC1, an RNA-binding protein involved in renal cystic diseases. The pathogenic effect of the ANKS3 mutation was validated in the zebrafish mutant and knock-in rat model, the latter showing urine concentration defect and tubular dilatations similar to NPH patients. In addition, cilia morphology and function as well as epithelialization of kidney tubular cells was affected by loss or mutation of ANKS3. Finally, our results evidenced that these classically renal ciliopathy associated phenotypes were linked to the negative regulation of BICC1 by ANKS3 which binds to transcripts of the major NPH gene NPHP1 and mediates their decay through the AGO2-RISC complex and recruitment into P-bodies. Altogether, our findings suggest that the ANKS3/BICC1 complex is a key post-transcriptional regulator of NPHP1 transcript stability, providing another level of regulation of cilium biogenesis and kidney homeostasis, as well as an unusual mechanism leading to NPH-related ciliopathies.

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Section: Discussionmentioning

confidence: 63%

The ANKS3/BICC1 protein complex is a master post-transcriptional regulator ofNPHP1ciliopathy-gene transcripts

Mahuzier,

Odye,

Grampa

et al. 2024

Preprint

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“…One study screened a library of 273 kinase inhibitors and identified thiazovivin (a pyrimidine-based non-selective ROCK inhibitor) as a significant hit (63). It is also interesting to note that the plant flavanoid, eupatilin, which was highlighted as a potential therapeutic for CEP290 -related retinal dystrophy (11) and has been used to treat the Rpgrip1l -/- mouse (64), has an indirect effect on actin cytoskeleton remodelling that is mediated by CEP290 (65). Several other screens have identified other biological targets for the restoration of cilia, for example a screen to identify drugs that restore cilia expression in cancer cells identified 118 compounds, many of which affect levels of cAMP, calcium or other ions (66).…”

Section: Discussionmentioning

confidence: 99%

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Lake¹,

Smith²,

Natarajan³

et al. 2020

Preprint

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Primary cilia are microtubule-based organelles that act as cellular antennae to mediate vertebrate development and growth factor signalling. Defects in primary cilia result in a group of inherited developmental conditions known as ciliopathies. Ciliopathies often present with cystic kidney disease, a major cause of early renal failure that requires renal replacement therapies. Currently, only one drug, Tolvaptan, is licensed to slow the decline of renal function for the ciliopathy polycystic kidney disease. Novel therapeutic interventions for these conditions remain a pressing clinical need.We screened clinical development compounds for positive effects on cilia formation and function and identified fasudil hydrochloride as the top hit. Fasudil is a generic, off-patent drug that is a potent but broadly selective Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor. In a parallel whole genome siRNA-based reverse genetics phenotypic screen of positive modulators of cilia formation, we identified ROCK2 as the target molecule. We demonstrate that ROCK2 is a key mediator of cilium formation and function through effects on actin cytoskeleton remodelling. Our results indicate that specific ROCK2 inhibitors such as belumosudil (KD-025) could be repurposed for pharmacological intervention in cystic kidney disease. We propose that ROCK2 inhibition represents a novel, disease-modifying therapeutic approach for heterogeneous ciliopathies.

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“…Eupatilin, a compound able to rescue ciliogenesis in CEP290 invalidated cells (see below), directly modulates the calmodulin/NPHP5 interaction therefore increasing the amount of NPHP5 at the transition zone in the absence of CEP90 ( Kim et al, 2018 ). Interestingly, Eupatilin was recently shown to improve cilia-related phenotypes in the context of RPGRIP1L/NPHP8 suggesting that it might present broader potential in transition zone-related NPH ( Wiegering et al, 2021 ).…”

Section: Pharmacotherapymentioning

confidence: 99%

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Stokman

Saunier

Benmerah

2021

Front. Cell Dev. Biol.

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Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

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Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Cited by 4 publications

References 93 publications

The ANKS3/BICC1 protein complex is a master post-transcriptional regulator ofNPHP1ciliopathy-gene transcripts

The ANKS3/BICC1 protein complex is a master post-transcriptional regulator ofNPHP1ciliopathy-gene transcripts

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

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